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ADVERSE REACTIONS

6.1 Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Treatment of Osteoporosis in Postmenopausal Women

The safety of Reclast in the treatment of postmenopausal osteoporosis was assessed in Study 1, a large, randomized, double-blind, placebo-controlled, multinational study of 7736 postmenopausal women aged 65-89 years with osteoporosis, diagnosed by bone mineral density or the presence of a prevalent vertebral fracture. The duration of the trial was three years with 3862 patients exposed to Reclast and 3852 patients exposed to placebo administered once annually as a single 5 mg dose in 100 mL solution infused over at least 15 minutes, for a total of three doses. All women received 1000 to 1500 mg of elemental calcium plus 400 to 1200 IU of vitamin D supplementation per day.

The incidence of all-cause mortality was similar between groups: 3.4% in the Reclast group and 2.9% in the placebo group. The incidence of serious adverse events was 29.2% in the Reclast group and 30.1% in the placebo group. The percentage of patients who withdrew from the study due to adverse events was 5.4% and 4.8% for the Reclast and placebo groups, respectively.

The safety of Reclast in the treatment of osteoporosis patients with a recent (within 90 days) low-trauma hip fracture was assessed in Study 2, a randomized, double-blind, placebo-controlled, multinational endpoint-driven study of 2127 men and women aged 50-95 years 1065 patients were randomized to Reclast and 1062 patients were randomized to placebo. Reclast was administered once annually as a single 5 mg dose in 100 mL solution infused over at least 15 minutes. The study continued until at least 211 patients had a confirmed clinical fracture in the study population who were followed for an average of approximately 2 years on study drug. Vitamin D levels were not routinely measured but a loading dose of vitamin D (50,000 to 125,000 IU orally or IM) was given to patients and they were started on 1000 to 1500 mg of elemental calcium plus 800 to 1200 IU of vitamin D supplementation per day for at least 14 days prior to the study drug infusions.

The incidence of all-cause mortality was 9.6% in the Reclast group and 13.3% in the placebo group. The incidence of serious adverse events was 38.3% in the Reclast group and 41.3% in the placebo group. The percentage of patients who withdrew from the study due to adverse events was 5.3% and 4.7% for the Reclast and placebo groups, respectively.

Adverse reactions reported in at least 2% of patients with osteoporosis and more frequently in the Reclast-treated patients than placebo-treated patients in either osteoporosis trial are shown below in Table 1.

Table 1. Adverse Reactions Occurring in ≥ 2.0% of Patients with Osteoporosis and More Frequently than in Placebo-Treated Patients

Study 1

Study 2

System Organ Class

5 mg IV Reclastonce per year %(N=3862)

Placebo once per year%(N=3852)

5 mg IV Reclastonce per year %(N=1054)

Placebo once per year%(N=1057)

Blood and the Lymphatic System Disorders

Anemia

4.4

3.6

5.3

5.2

Metabolism and Nutrition Disorders

Dehydration

0.6

0.6

2.5

2.3

Anorexia

2.0

1.1

1.0

1.0

Nervous System Disorders

Headache

12.4

8.1

3.9

2.5

Dizziness

7.6

6.7

2.0

4.0

Ear and Labyrinth Disorders

Vertigo

4.3

4.0

1.3

1.7

Cardiac Disorders

Atrial Fibrillation

2.4

1.9

2.8

2.6

Vascular Disorders

Hypertension

12.7

12.4

6.8

5.4

Gastrointestinal Disorders

Nausea

8.5

5.2

4.5

4.5

Diarrhea

6.0

5.6

5.2

4.7

Vomiting

4.6

3.2

3.4

3.4

Abdominal Pain Upper

4.6

3.1

0.9

1.5

Dyspepsia

4.3

4.0

1.7

1.6

Musculoskeletal, Connective Tissue and Bone Disorders

Arthralgia

23.8

20.4

17.9

18.3

Myalgia

11.7

3.7

4.9

2.7

Pain in Extremity

11.3

9.9

5.9

4.8

Shoulder Pain

6.9

5.6

0.0

0.0

Bone Pain

5.8

2.3

3.2

1.0

Neck Pain

4.4

3.8

1.4

1.1

Muscle Spasms

3.7

3.4

1.5

1.7

Osteoarthritis

9.1

9.7

5.7

4.5

Musculoskeletal Pain

0.4

0.3

3.1

1.2

General Disorders and Administrative Site Conditions

Pyrexia

17.9

4.6

8.7

3.1

Influenza-like Illness

8.8

2.7

0.8

0.4

Fatigue

5.4

3.5

2.1

1.2

Chills

5.4

1.0

1.5

0.5

Asthenia

5.3

2.9

3.2

3.0

Peripheral Edema

4.6

4.2

5.5

5.3

Pain

3.3

1.3

1.5

0.5

Malaise

2.0

1.0

1.1

0.5

Hyperthermia

0.3

<0.1

2.3

0.3

Chest Pain

1.3

1.1

2.4

1.8

Investigations

Creatinine Renal Clearance Decreased

2.0

2.4

2.1

1.7

Renal Impairment

Treatment with intravenous bisphosphonates, including zoledronic acid, has been associated with renal impairment manifested as deterioration in renal function (i.e., increased serum creatinine) and in rare cases, acute renal failure. In the clinical trial for postmenopausal osteoporosis, patients with baseline creatinine clearance < 30 mL/min, urine dipstick ≥2+ protein or increase in serum creatinine of >0.5 mg/dL during the screening visits were excluded. The change in creatinine clearance (measured annually prior to dosing) and the incidence of renal failure and impairment was comparable for both the Reclast and placebo treatment groups over 3 years, including patients with mild to moderate renal impairment (creatinine clearance between 30-60 mL/min) at baseline. Overall, there was a transient increase in serum creatinine observed within 10 days of dosing in 1.8% of Reclast-treated patients versus 0.8% of placebo-treated patients which resolved without specific therapy [s ee Warnings and Precautions (5.3) ].

Acute Phase Reaction

The signs and symptoms of acute phase reaction occurred in Study 1 following Reclast infusion including, fever (18%), myalgia (9%), and flu-like symptoms (8%), headache (7%), and arthralgia (7%). The majority of these symptoms occurred within the first 3 days following the dose of Reclast and usually resolved within 3 days of onset but resolution could take up to 7-14 days. In Study 2, patients without a contraindication to acetaminophen were provided with a standard oral dose at the time of the IV infusion and instructed to use additional acetaminophen at home for the next 72 hours as needed. Reclast was associated with fewer signs and symptoms of a transient acute phase reaction in this trial: fever (7%) and arthralgia (3%). The incidence of these symptoms decreased with subsequent doses of Reclast.

Laboratory Findings

In Study 1, in women with postmenopausal osteoporosis, approximately 0.2% of patients had notable declines of serum calcium levels (less than 7.5 mg/dL) following Reclast administration. No symptomatic cases of hypocalcemia were observed. In Study 2, following pre-treatment with vitamin D, no patients had treatment emergent serum calcium levels below 7.5 mg/dL.

Injection Site Reactions

In the osteoporosis trials, local reactions at the infusion site such as itching, redness and/or pain have been reported in 0 to 0.7% of patients following the administration of Reclast and 0 to 0.5% of patients following administration of placebo.

Osteonecrosis of the Jaw

In the postmenopausal osteoporosis trial, Study 1, in 7736 patients, after initiation of therapy, symptoms consistent with ONJ occurred in one patient treated with placebo and one patient treated with Reclast. Both cases resolved after appropriate treatment [s ee Warnings and Precautions (5.4) ]. No reports of osteonecrosis of the jaw were reported in either treatment group in Study 2.

Atrial Fibrillation

In the postmenopausal osteoporosis trial, Study 1, adjudicated serious adverse events of atrial fibrillation in the zoledronic acid treatment group occurred in 1.3% of patients (50 out of 3862) compared to 0.4% (17 out of 3852) in the placebo group. The overall incidence of all atrial fibrillation adverse events in the zoledronic acid treatment group was reported in 2.5% of patients (96 out of 3862) in the Reclast group vs. 1.9% of patients (75 out of 3852) in the placebo group. Over 90% of these events in both treatment groups occurred more than a month after the infusion. In an ECG sub-study, ECG measurements were performed on a subset of 559 patients before and 9 to 11 days after treatment. There was no difference in the incidence of atrial fibrillation between treatment groups suggesting these events were not related to the acute infusions. In Study 2, adjudicated serious adverse events of atrial fibrillation in the zoledronic acid treatment group occurred in 1.0% of patients (11 out of 1054) compared to 1.2% (13 out of 1057) in the placebo group demonstrating no difference between treatment groups.

Ocular Adverse Events

Cases of iritis/uveitis/episcleritis/conjunctivitis have been reported in patients treated with bisphosphonates, including zoledronic acid. In the osteoporosis trials, 1 (<0.1%) to 9 (0.2%) patients treated with Reclast and 0 (0%) to 1 (<0.1%) patient treated with placebo developed iritis/uveitis/episcleritis.

Osteoporosis in Men

The safety of Reclast in men with osteoporosis or osteoporosis secondary to hypogonadism, was assessed in a two year randomized, multicenter, double-blind, active controlled group study of 302 men aged 25-86 years. One hundred fifty three (153) patients were exposed to Reclast administered once annually with a 5 mg dose in 100 mL infused over 15 minutes for up to a total of two doses, and 148 patients were exposed to a commercially-available oral weekly bisphosphonate (active control) for up to two years. All participants received 1000 mg of elemental calcium plus 800 to 1000 IU of vitamin D supplementation per day.

The incidence of all-cause mortality (one in each group) and serious adverse events were similar between the Reclast and active control treatment groups. The percentage of patients experiencing at least one adverse event was comparable between the Reclast and active control groups, with the exception of a higher incidence of post-dose symptoms in the Reclast group that occurred within 3 days after infusion. The overall safety and tolerability of Reclast was similar to the active control.

Adverse reactions reported in at least 2% of men with osteoporosis and more frequently in the Reclast-treated patients than the active control-treated patients and either (1) not reported in the postmenopausal osteoporosis trial or (2) reported more frequently in the trial of osteoporosis in men are presented in Table 2. Therefore, Table 2 should be viewed in conjunction with Table 1.

Table 2: Adverse Reactions Occurring in > 2% of Men with Osteoporosis and More Frequently in the Reclast-Treated Patients than the Active Control -Treated Patients and either (1) Not Reported in the Postmenopausal Osteoporosis Trial or (2) Reported More Frequently in this Trial

Creatinine clearance was measured annually prior to dosing and changes in long-term renal function over 24 months was comparable in the Reclast and active control groups. [ See Warnings and Precautions (5.3) ].

Acute Phase Reaction

Reclast was associated with signs and symptoms of an acute phase reaction: Myalgia (17.1%), fever (15.7%), fatigue (12.4%), arthralgia (11.1%), pain (10.5%), chills (9.8%), headache (9.8%), influenza-like illness (8.5%), malaise (5.2%), and back pain (3.3%), which occurred within the first 3 days following the dose of Reclast. The majority of these symptoms were mild to moderate and resolved within 3 days of the event onset but resolution could take up to 7-14 days. The incidence of these symptoms decreased with subsequent doses of Reclast.

Atrial Fibrillation

The incidence of all atrial fibrillation adverse events in the Reclast treatment group was 3.3% (5 out of 153) compared to 2.0% (3 out of 148) in the active control group. However, there were no patients with adjudicated serious adverse events of atrial fibrillation in the Reclast treatment group.

Laboratory Findings

There were no patients who had treatment emergent serum calcium levels below 7.5 mg/dL.

Injection Site Reactions

There were 4 patients (2.6%) on Reclast vs. 2 patients (1.4%) on active control with local site reactions.

Osteonecrosis of the Jaw

In this trial there were no cases of osteonecrosis of the jaw. [ See Warnings and Precautions (5.4) ].

Glucocorticoid-Induced Osteoporosis

The safety of Reclast in men and women in the treatment and prevention of glucocorticoid-induced osteoporosis was assessed in a randomized, multicenter, double-blind, active controlled, stratified study of 833 men and women aged 18-85 years treated with > 7.5 mg/day oral prednisone (or equivalent). Patients were stratified according to the duration of their pre-study corticosteroid therapy: < 3 months prior to randomization (prevention subpopulation), and > 3 months prior to randomization (treatment subpopulation).

The duration of the trial was one year with 416 patients exposed to Reclast administered once as a single 5 mg dose in 100 mL infused over 15 minutes, and 417 patients exposed to a commercially-available oral daily bisphosphonate (active control) for one year. All participants received 1000 mg of elemental calcium plus 400 to 1000 IU of vitamin D supplementation per day.

The incidence of all–cause mortality was similar between treatment groups: 0.9% in the Reclast group and 0.7% in the active control group. The incidence of serious adverse events was similar between the Reclast treatment and prevention groups, 18.4% and 18.1%, respectively, and the active control treatment and prevention groups, 19.8% and 16.0%, respectively. The percentage of subjects who withdrew from the study due to adverse events was 2.2% in the Reclast group vs. 1.4% in the active control group. The overall safety and tolerability were similar between Reclast and active control groups with the exception of a higher incidence of post-dose symptoms in the Reclast group that occurred within 3 days after infusion. The overall safety and tolerability profile of Reclast in glucocorticoid-induced osteoporosis was similar to the adverse events reported in the Reclast postmenopausal osteoporosis clinical trial.

Adverse reactions reported in at least 2% of patients that were either not reported in the postmenopausal osteoporosis trial or reported more frequently in the treatment and prevention of glucocorticoid-induced osteoporosis trial included the following: abdominal pain (Reclast 7.5%; active control 5.0%), and musculoskeletal pain (Reclast 3.1%; active control 1.7%). Other musculoskeletal events included back pain (Reclast 4.3%, active control 6.2%), bone pain (Reclast 3.1%, active control 2.2%), and pain in the extremity (Reclast 3.1%, active control 1.2%). In addition, the following adverse events occurred more frequently than in the postmenopausal osteoporosis trial: nausea (Reclast 9.6%; active control 8.4%), and dyspepsia (Reclast 5.5%; active control 4.3%).

Renal Impairment

Renal function measured prior to dosing and at the end of the 12 month study was comparable in the Reclast and active control groups. [ See Warnings and Precautions (5.3) ].

Acute Phase Reaction

Reclast was associated with signs and symptoms of a transient acute phase reaction that was similar to that seen in the Reclast postmenopausal osteoporosis clinical trial.

Atrial Fibrillation

The incidence of atrial fibrillation adverse events was 0.7% (3 of 416) in the Reclast group compared to no adverse events in the active control group. All subjects had a prior history of atrial fibrillation and no cases were adjudicated as serious adverse events. One patient had atrial flutter in the active control group.

Laboratory Findings

There were no patients who had treatment emergent serum calcium levels below 7.5 mg/dL.

Injection Site Reactions

There were no local reactions at the infusion site.

Osteonecrosis of the Jaw

In this trial there were no cases of osteonecrosis of the jaw. [ See Warnings and Precautions (5.4) ].

Paget’s Disease of Bone

In the Paget’s disease trials, two 6-month, double-blind, comparative, multinational studies of 349 men and women aged > 30 years with moderate to severe disease and with confirmed Paget’s disease of bone, 177 patients were exposed to Reclast and 172 patients exposed to risedronate. Reclast was administered once as a single 5 mg dose in 100 mL solution infused over at least 15 minutes. Risedronate was given as an oral daily dose of 30 mg for 2 months.

The incidence of serious adverse events was 5.1% in the Reclast group and 6.4% in the risedronate group. The percentage of patients who withdrew from the study due to adverse events was 1.7% and 1.2% for the Reclast and risedronate groups, respectively.

Adverse reactions occurring in at least 2% of the Paget’s patients receiving Reclast (single 5 mg IV infusion) or risedronate (30 mg oral daily dose for 2 months) over a 6-month study period are listed by system organ class in Table 3.

In the Paget’s disease trials, early, transient decreases in serum calcium and phosphate levels were observed. Approximately 21% of patients had serum calcium levels <8.4 mg/dL 9-11 days following Reclast administration.

Renal Impairment

In clinical trials in Paget’s disease there were no cases of renal deterioration following a single 5 mg 15-minute infusion [s ee Warnings and Precautions (5.3) ].

Acute Phase Reaction

The signs and symptoms of acute phase reaction (influenza-like illness, pyrexia, myalgia, arthralgia, and bone pain) were reported in 25% of patients in the Reclast-treated group compared to 8% in the risedronate-treated group. Symptoms usually occur within the first 3 days following Reclast administration. The majority of these symptoms resolved within 4 days of onset.

Osteonecrosis of the Jaw

Osteonecrosis of the jaw has been reported with zoledronic acid [ see Warnings and Precautions (5.4) ].

6.2 Post-Marketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following adverse reactions have been identified during post approval use of Reclast:

Acute Phase Reactions

Fever, headache, flu-like symptoms, nausea, vomiting, diarrhea, arthralgia, and myalgia. Symptoms may be significant and lead to dehydration.

There have been rare reports of allergic reaction with intravenous zoledronic acid including urticaria, angioedema, and bronchoconstriction. Rare cases of anaphylactic reaction/shock have also been reported.

Other

Hypocalcemia

REPORTS OF SUSPECTED RECLAST SIDE EFFECTS / ADVERSE REACTIONS

Below is a sample of reports where side effects / adverse reactions may be related to Reclast. The information is not vetted and should not be considered as verified clinical evidence.

Possible Reclast side effects / adverse reactions in 62 year old female

Reported by a consumer/non-health professional from United States on 2011-10-03